4-89895101-G-A

Position:

• chr4-89895101-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The ENST00000264790.7(MMRN1):​c.130G>A​(p.Val44Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00202 in 1,613,824 control chromosomes in the GnomAD database, including 61 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.011 (35 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (26 hom.)
• Consequence: MMRN1 ENST00000264790.7 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0550

Genes affected

MMRN1 (HGNC:7178): (multimerin 1) Multimerin is a massive, soluble protein found in platelets and in the endothelium of blood vessels. It is comprised of subunits linked by interchain disulfide bonds to form large, variably sized homomultimers. Multimerin is a factor V/Va-binding protein and may function as a carrier protein for platelet factor V. It may also have functions as an extracellular matrix or adhesive protein. Recently, patients with an unusual autosomal-dominant bleeding disorder (factor V Quebec) were found to have a deficiency of platelet multimerin. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.002287656).
• BP6: Variant 4-89895101-G-A is Benign according to our data. Variant chr4-89895101-G-A is described in ClinVar as [Benign]. Clinvar id is 785103.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0112 (1700/152160) while in subpopulation AFR AF= 0.0382 (1585/41518). AF 95% confidence interval is 0.0366. There are 35 homozygotes in gnomad4. There are 755 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 35 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MMRN1	NM_007351.3	c.130G>A	p.Val44Ile	missense_variant	1/8	ENST00000264790.7	NP_031377.2
MMRN1	NM_001371403.1	c.130G>A	p.Val44Ile	missense_variant	2/9		NP_001358332.1
MMRN1	XM_047449831.1	c.130G>A	p.Val44Ile	missense_variant	2/8		XP_047305787.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MMRN1	ENST00000264790.7	c.130G>A	p.Val44Ile	missense_variant	1/8	1	NM_007351.3	ENSP00000264790	P1
MMRN1	ENST00000394980.5	c.130G>A	p.Val44Ile	missense_variant	2/9	5		ENSP00000378431	P1

Frequencies

GnomAD3 genomes AF: 0.0112 AC: 1697 AN: 152042 Hom.: 35 Cov.: 32

Gnomad AFR AF: 0.0382

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00577

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00957

GnomAD3 exomes AF: 0.00307 AC: 769 AN: 250416 Hom.: 12 AF XY: 0.00222 AC XY: 300 AN XY: 135332

Gnomad AFR exome AF: 0.0420

Gnomad AMR exome AF: 0.00209

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000709

Gnomad OTH exome AF: 0.00115

GnomAD4 exome AF: 0.00107 AC: 1565 AN: 1461664 Hom.: 26 Cov.: 34 AF XY: 0.000912 AC XY: 663 AN XY: 727132

Gnomad4 AFR exome AF: 0.0372

Gnomad4 AMR exome AF: 0.00235

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000351

Gnomad4 OTH exome AF: 0.00280

GnomAD4 genome AF: 0.0112 AC: 1700 AN: 152160 Hom.: 35 Cov.: 32 AF XY: 0.0102 AC XY: 755 AN XY: 74374

Gnomad4 AFR AF: 0.0382

Gnomad4 AMR AF: 0.00576

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.00947

Alfa AF: 0.00442 Hom.: 7

Bravo AF: 0.0127

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0379 AC: 167

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00357 AC: 433

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000119

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Apr 04, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	2.1
DANN	Benign	0.97
DEOGEN2	Benign	0.028	T;T
Eigen	Benign	-0.82
Eigen_PC	Benign	-0.93
FATHMM_MKL	Benign	0.022	N
LIST_S2	Benign	0.42	.;T
MetaRNN	Benign	0.0023	T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	2.0	M;M
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-0.14	N;N
REVEL	Benign	0.068
Sift	Benign	0.085	T;T
Sift4G	Benign	0.15	T;T
Polyphen		0.43	B;B
Vest4		0.021
MVP		0.25
MPC		0.012
ClinPred		0.0028	T
GERP RS		-0.34
Varity_R		0.025
gMVP		0.11

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1442139; hg19: chr4-90816252;